A major challenge facing nanotechnology research is the development of smarter and more powerful carriers for the effective delivery of pharmaceutical agents. In particular, formulating complex pharmaceutical agents such as proteins, peptides and lipophilic molecules, with nanocarriers is often required so as to overcome physicochemical limitations and thereby attain the full pharmaceutical potential of the molecules [1]. To this end, lipid-based compositions (eg liposomes and solid lipid nanoparticles) which encapsulate pharmaceutical agents have been the most widely investigated and, indeed, some compositions of this type have been adopted in certain drug delivery applications (eg oral delivery of poorly water soluble drugs, anti-cancer formulations and vaccinations). However, even though lipid-based compositions can offer high levels of biocompatibility, favourable pharmacokinetic profiles and a relatively simple manufacture, to date the clinical use of such compositions has been somewhat limited due to instability, insufficient drug loading and/or characteristic “burst” release profiles of the encapsulated pharmaceutical agents [2-6].
An alternative approach to the formulation of pharmaceutical agents with nanocarriers involves the use of polymeric nanoparticles. Such nanoparticles have been investigated for use in the encapsulation of pharmaceutical agents with poor solubility and permeability, and have been found to provide higher levels of stability in biological fluid (ie. relative to lipid-based systems) while offering the possibility of a controlled rate of release of the pharmaceutical agent in a manner enabling effective drug delivery. However, the biocompatibility of many polymeric nanoparticles is not as high as lipid systems [7-9] and, consequently, considerable research effort has been devoted to engineering novel nanostructured carrier systems which might combine the advantages of lipid-based systems with those of polymeric nanoparticles, whilst minimising the physicochemical and biological limitations of the two nanocarriers.
A wide range of “hybrid” polymer-lipid nanocomposites have been recently reported which aim to address multi-faceted drug delivery challenges [10-13, 45]. The most extensively fabricated type of hybrid particle consists of a lipid shell-polymer core architecture commonly assembled via a two-step method whereby anionic poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles are mixed with cationic liposomes at a desired ratio [1, 14, 15]. However, single-step methods also exist which minimise batch-to-batch variation of physicochemical properties. Such methods utilise phospholipids as emulsifiers in the nanoparticle synthesis, resulting in the self-assembly of lipid-coated polymer nanoparticles [11, 16]. PLGA is an FDA-approved biodegradable polymer that has received the most extensive attention in the field of polymer-lipid hybrids due to its biocompatibility [17]. Lipid shell-polymer core morphology of PLGA-lipid hybrids have demonstrated several potential advantages over conventional delivery systems such as controllable particle size for high uptake, surface functionality for targeted delivery, high drug loading, entrapment of multiple pharmaceutical agents for combination therapies and “tunable” drug release profiles [12]. However, limitations are still present in such systems in regard to the stability of the lipid component and the burst release profiles from agents encapsulated within the lipid shell.
Previously, the present applicant developed a novel nanostructured lipid carrier system which consists of lipid encapsulated within a three-dimensional porous silica matrix or coacervate; providing silica-lipid hybrid (SLH) microparticles [18-20]. These SLH microparticles can be prepared by spray drying a silica-stabilised emulsion, with the water removal process inducing the aggregation of silica particles into a sponge-like matrix, whereby oil droplets are attached by lipophilic negatively or positively charged surfactants [21]. The surfactant charge impacts the nanostructure of the dry SLH microparticles due to the enhanced stabilising effect of nanoparticles when a charge neutralisation mechanism is operative in a Pickering emulsion [18]. The oral absorption of a number of lipophilic drugs has been shown to increase as a result of increased solubility in SLH microparticles, due to the enhanced and controlled digestion of lipid adsorbed in the three-dimensional silica matrix by the digestive enzyme, lipase [22-24]. The increased interfacial surface area of lipid, binding support of hydrophilic silica and reduced interference effect of digestion products have been shown to enhance lipase adsorption and action in SLH microparticles [25]. However, the exact effect of the surface chemistry of the solid matrix support on the digestibility of the encapsulated lipid is not well understood.
The ability to form hybrid microstructures with porous three-dimensional matrices whereby lipid is adsorbed may be controlled initially by the ability of solid nanoparticles to form a stable emulsion with medium chain triglycerides (MCT). PLGA nanoparticles with a slight negative surface charge, due to the use of PVA as a stabiliser, have shown the ability to impart kinetic stability to a range of non-polar oils by forming weak interactions with the oil-water interface [26]. Herein, the present applicant investigated whether the stabilising and controlled delivery characteristics of polymeric nanoparticles (such as PLGA nanoparticles) might be usefully combined with the solubilising effect of lipid droplets to form dry polymer (nanoparticle)-lipid hybrid (PLH) microparticles with a novel polymeric nanoparticle shell-lipid core architecture through the process of spray drying. Further, the present applicant investigated the use of a cryoprotectant (such as mannitol) in the spray drying step, and identified an additional form of dry PLH microparticles including the cryoprotectant (ie. polymer (nanoparticle)-lipid-cryoprotectant hybrid (PLCH) microparticles) with a novel architecture consisting of a three-dimensional matrix (or, in other words, coacervate) of the polymeric nanoparticles, lipid droplets and cryoprotectant.